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Chemical generation of bispecific antibodies

机译：化学生成双特异性抗体

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摘要

Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidi-none linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xeno-graft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.
机译：由于双特异性抗体（BsAbs）同时结合两种不同抗原的能力，它们被认为是有前途的治疗剂。已经开发了几种双特异性模态，但是由于稳定性和制造复杂性的问题，其效用受到限制。在这里，我们报告了一种基于支架抗体和药效团肽异源二聚体的通用技术，该技术能够快速生成双特异性抗体（称为双特异性CovX抗体）并对其进行化学优化。使用支链的氮杂环丁烷-酮连接子将两种不同的肽连接在一起，并在温和条件下以位点特异性方式与支架抗体融合。药效基团负责功能活性，而抗体支架具有长的半衰期和类似Ig的分布。可以对药效团进行化学优化或将其替换为其他药效团以产生优化的或独特的双特异性抗体。作为原型，我们开发了一种双特异性抗体，可同时结合血管内皮生长因子（VEGF）和血管生成素2（Ang2），抑制其功能，在肿瘤异种移植研究中显示功效，并大大增强了标准化学疗法的抗肿瘤作用。这种独特的抗血管生成双特异性抗体处于1期临床试验中。

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  • 作者

    Venkata R. Doppalapudi; Jie Huang; Dingguo Liu; Ping Jin; Bin Liu; Lingna Li; Joel Desharnais; Crystal Hagen; Nancy J. Levin; Michael J. Shields; Michelle Parish; Robert E. Murphy; Joselyn Del Rosario; Bryan D. Oates; Jing-Yu Lai; Maria J. Matin; Zemeda Ainekulu; Abhijit Bhat; Curt W. Bradshaw; Gary Woodnutt; Richard A. Lerner; Rodney W. Lappe;

  • 作者单位

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;

    CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    angiogensis; dual targeting; aldolase antibody; site selective conjugation;

    机译：血管生成;双重定位;醛缩酶抗体;选择性结合;

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